DESCRIPTION: (Verbatim from the Applicant's Abstract) It is becoming increasingly clear that similar neuronal networks are activated both normally during sleep and pathologically during the thalamocortical seizures that occur in generalized absence epilepsy. What determines whether the thalamocortical system acts in a normal or a pathological manner? Recent studies pinpoint the thalamic reticular nucleus as a key regulatory site in this process. The reticular nucleus is poised to intercept and act upon the ascending and descending flow of cortical information. The reticular nucleus is poised to intercept and act upon the ascending and descending flow of cortical information. Output from reticular neurons serves to inhibit thalamocortical relay neurons and shape sensory responses as well as to contribute to the generation of thalamocortical oscillations related to sleep and epilepsy. In mice with an inhibitory neurotransmitter receptor gene (GBRB3) inactivated, neurons in the thalamic reticular nucleus lose their ability to inhibit each other. This loss of inhibition is associated with a dramatic increase in epileptiform synchrony measured in vivo and in vitro with thalamic brain slices. Intra-reticular inhibition thus seems to normally produce distance-dependent differences in the timing of electrical responses across the extent of the thalamus. Elimination of such timing differences leads to pathological synchrony. In addition to structural changes in intra-reticular inhibition, dynamic changes, such as down-regulation via activation of presynaptic GABA B receptors can occur. This would promote seizures, but other GABA B receptor actions have the opposite effect. In this proposal, molecular, computational , and neurophysiological approaches, including knockdown and knockout experiments, will be used to test the hypothesis that recurrent connectivity between thalamic reticular cells prevents the hypersynchrony of absence epilepsy, and that collapse of the interconnectivity can promote seizure generation . To address the latter question, we will develop a strategy to specifically antagonize GABA B receptors that promote seizures, with the ultimate goal of improved treatment of absence epilepsies.